CN114163434B

CN114163434B - Preparation method of alkynyl-containing compound and intermediate thereof

Info

Publication number: CN114163434B
Application number: CN202111060516.1A
Authority: CN
Inventors: 温剑锋; 冯建鹏; 吴天助; 蔡民民; 滕尚军
Original assignee: Healthquest Pharma Inc; Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Current assignee: Healthquest Pharma Inc; Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Priority date: 2020-09-10
Filing date: 2021-09-10
Publication date: 2023-05-23
Anticipated expiration: 2041-09-10
Also published as: CN116514808A; WO2022053014A1; CN114163434A

Abstract

The present invention provides methods for preparing alkynyl-containing compounds of formula (I) and intermediates thereof, and related compounds, as shown below. Pharmaceutical compositions comprising the compounds and methods of treating cancer are also provided.

Description

Preparation method of alkynyl-containing compound and intermediate thereof

Technical Field

Provided herein are methods of making compounds containing alkynyl moieties and methods of using the same for the treatment of cancer. Certain compounds related to the methods are also provided.

Background

Cancer has a significant impact on society worldwide. Cancer is the second most common cause of death in humans following cardiovascular disease. The national cancer institute estimated that in 2015, approximately 1,658,370 new cancer cases were diagnosed in the united states and 589,430 people died from the disease.

Chronic Myelogenous Leukemia (CML) is a cancer that begins with certain hematopoietic cells of the bone marrow. CML cells contain the abnormal gene BCR-ABL, resulting in uncontrolled growth and proliferation of CML cells. BCR-ABL is a protein known as tyrosine kinase. Tyrosine Kinase Inhibitors (TKIs) targeting BCR-ABL are standard therapies for CML.

Imatinib

Is the first drug for specifically targeting BCR-ABL tyrosine kinase protein to treat CML. However, newly emerging acquired resistance to imatinib has become a major challenge for clinical management of CML. More than 100 drug resistance-associated BCR-ABL mutants have been clinically identified, with "gatekeeper" T315I being the most common mutant, accounting for about 15-20% of all clinically available mutants. Ren et al, J.Med chem.2013,56,879-894.

Efforts have been made to identify new BCR-ABL inhibitors to overcome imatinib resistance. Compound 6 is a novel orally bioavailable Bcr-Abl inhibitor that is effective against broad-spectrum expression of drug mutants including T3151. Compound 6 and its preparation are described in PCT publication WO 2012/000304. However, the preparation method of compound 6 disclosed in WO2012/000304 involves a large number of synthesis steps, a large number of chemical reagent types, and severe reaction conditions, including purification by high-performance liquid chromatography using a pressure-resistant sealed tube in each synthesis step. Thus, the known methods limit mass production.

Thus, there is a need for an efficient and cost-effective route to compound 6. The invention provides a novel method for preparing the compound 6, which has mild reaction conditions, can obtain higher yield and can be used for large-scale industrial production.

Disclosure of Invention

In certain embodiments, provided herein are methods for preparing a compound of formula (I'):

wherein the process comprises reacting a compound of formula (II ') with a compound of formula (III) to provide a compound of formula (I'), as shown in scheme VI below:

scheme VI:

wherein R is ₁ ,R ₂ ,R ₃ ,R ₇ ,R ₈ ,R ₉ And R is ₁₀ As defined herein or elsewhere.

In certain embodiments, provided herein is a method of preparing a compound of formula (I):

wherein the process comprises reacting a compound of formula (II) with a compound of formula (III) to provide a compound of formula (I), as shown in scheme I below:

scheme I:

wherein R is ₁ 、R ₂ And R is ₃ As defined herein or elsewhere.

In certain embodiments, provided herein are methods of preparing compound 6 having the structure:

wherein the method comprises reacting a compound of formula 4 and a compound of formula 5 to provide compound 6 or a pharmaceutically acceptable salt thereof, as shown in scheme V below:

scheme V:

in some embodiments, the methods described in schemes I-VII are amidation reactions performed under nitrogen or inert gas

And/or, in the amidation reaction, the solvent includes an ether solvent, DMF, N-dimethylacetamide, DMSO, N-methylpyrrolidone, toluene or acetonitrile;

And/or in the amidation reaction, the volume/mass ratio of the solvent to the compound of formula (II') or (II) or formula 4 is (about 5 to about 17) mL:1g;

and/or, in the amidation reaction, the base is an organic base and/or an inorganic base;

and/or in the amidation reaction, the molar ratio of base to compound of formula (II') or (II) or formula 4 is (about 1.5 to about 10): 1;

and/or, in the amidation reaction, adding the base in batches to the mixture of the remaining materials;

and/or in the amidation reaction, the molar ratio of the compound of formula (III) or formula 5 to the compound of formula (II') or (II) or formula 4 is (about 0.8 to about 1.5): 1, a step of;

and/or, in the amidation reaction, the reaction temperature of the amidation reaction is in the range of about-80 ℃ to about 10 ℃;

and/or, in the amidation reaction, optionally, the post-treatment of the amidation reaction includes washing the reaction solution with water and/or brine.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The term "about" is used herein to mean about, within the scope of, approximately, or approximately. When the term "about" is used in connection with a range of values, it modifies that range by extending the boundaries above and below the specified values. In general, the term "about" is used herein to modify values above and below the 10% variance of the values.

The term "comprising" means "including but not limited to".

As used herein, the terms "treat," "treating" and "treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, including but not limited to therapeutic benefits. In some embodiments, the treatment is performed after one or more symptoms have occurred. In some embodiments, the treatment may be performed without symptoms. For embodiments, the subject may be treated prior to the appearance of symptoms (e.g., based on a history of symptoms and/or based on genetic or other predisposition factors), or may continue after the symptoms are resolved, so that the embodiment prevents or delays recurrence.

Therapeutic benefits include eradication and/or amelioration of the underlying disease being treated, such as cancer; it also includes eradicating and/or ameliorating one or more symptoms associated with the underlying disorder such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder. In some embodiments, "treating" or "treatment" includes one or more of the following: (a) Inhibiting the disorder (e.g., alleviating one or more symptoms caused by the disorder, and/or alleviating the extent of the disorder); (b) Slowing or arresting the development of one or more symptoms associated with the disease (e.g., stabilizing the disease and/or slowing the progression or worsening of the disease); and/or (c) alleviating the disease (e.g., causing regression of clinical symptoms, ameliorating the disease, slowing the progression of the disease, and/or improving quality of life).

As used herein, "administering" or "administration" of a compound provided herein, e.g., a compound of formula 6 or a pharmaceutically acceptable salt thereof, includes delivering the compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, to a patient using any suitable formulation or route of administration, e.g., as described herein.

As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit the desired biological or medical response, including when administered to a subject to treat a disease, the amount of compound being sufficient to effect treatment of such disease. The effective amount will vary depending on the condition, its severity, the age, weight, etc., of the subject to be treated. An effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount may be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result can or has been achieved. Due to the combined, additive or synergistic effect of the compounds, the appropriate dosage of any co-administered compounds may optionally be reduced.

As used herein, a "patient" contemplated for administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and/or other primates (e.g., cynomolgus, rhesus).

As used herein, "pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences,1977,66,1-19 by S.M. berge et al. Pharmaceutically acceptable salts of compound 6 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art, for example ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionic acid salts, digluconate, dodecylsulfuric acid salts, ethanesulfonic acid salts, formic acid salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconic acid salts, hemisulfate salts, heptanoic acid salts, caproic acid salts, hydroiodic acid salts, 2-hydroxyethanesulfonic acid salts, lactobionic acid salts, lactic acid salts, lauric acid salts, dodecylsulfuric acid salts, malic acid salts, maleic acid salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinic acid salts, nitrate salts, oleic acid salts, oxalic acid salts, palmitoleic acid salts, pamoic acid salts, pectic acid salts, persulfates, 3-phenylpropionic acid salts, phosphate salts, pivalic acid salts, propionic acid salts, stearic acid salts, succinic acid salts, sulfuric acid salts, p-toluenesulfonic acid salts, undecanoic acid salts, valeric acid salts, and the like. While pharmaceutically acceptable counterions will be preferred for use in preparing pharmaceutical formulations, other anions are fully acceptable as synthetic intermediates. Thus, when these salts are chemical intermediates, they may be pharmaceutically undesirable anions such as iodide, oxalate, triflate, and the like.

In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of formula (I') or (I)) and a pharmaceutically acceptable excipient. In some embodiments, provided herein are pharmaceutical compositions comprising a compound of formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiments, provided herein are pharmaceutical compositions comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I') or (I))) or a pharmaceutical composition provided herein. In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising a compound of formula (I') or (I) and optionally a pharmaceutically acceptable excipient in the manufacture of a medicament for treating cancer. In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient in the manufacture of a medicament for treating cancer.

In some embodiments, the cancer is a hematological malignancy. In certain embodiments, the hematological malignancy is leukemia. In certain embodiments, the hematological malignancy is chronic myelogenous leukemia.

In certain embodiments, the patient has chronic myelogenous leukemia that is resistant to current tyrosine kinase inhibitor therapies. In some embodiments, the chronic myelogenous leukemia patient with resistance to current tyrosine kinase inhibitor therapy is caused by BCR-ABL mutation. In certain embodiments, the BCR-ABL mutation is T315I, E K/V, G250E, H396P, M351T, Q252H, Y253F/H or BCR-ABL ^WT Mutation. In certain embodiments, the BCR-ABL mutation is a T315I mutation.

In some embodiments, disclosed herein are high purity compounds of formula (I') prepared by the process shown in scheme VI. In some embodiments, disclosed herein are high purity compounds of formula (I) prepared by the process shown in scheme I. In certain embodiments, disclosed herein is high purity compound 6 prepared by the method shown in scheme V. In some embodiments, disclosed herein are high purity compounds of formula (I') prepared by the process shown in scheme VI. In some embodiments, disclosed herein are methods for preparing high purity compounds of formula (I) by the methods shown in scheme I. In certain embodiments, disclosed herein is high purity compound 6 prepared by the method shown in scheme V.

In certain embodiments, the pharmaceutical composition comprising a compound of formula (I') or (I) is administered once every 1 day, 2 days, or 3 days during the treatment cycle. The treatment period may be 20-40 days, preferably 25-35 days, more preferably 28 days. In certain embodiments, the pharmaceutical composition comprising compound 6 is administered once every 1 day, 2 days, or 3 days during the treatment cycle. The treatment period may be 20-40 days. Preferably 25-35 days, more preferably 28 days of treatment cycle.

In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises a compound of formula (I') or (I) in an amount of about 30mg, about 40mg, or about 45 mg. In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises compound 6 in an amount of about 30mg, about 40mg, or about 45 mg.

In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises a compound of formula (I') or (I) in an amount of about 50mg or about 60 mg. In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises compound 6 in an amount of about 50mg or about 60 mg.

In certain embodiments, the pharmaceutical composition is formulated as a dosage unit for daily administration, or once every other day (QOD), or once every third day, particularly once every other day.

The pharmaceutical compositions provided herein for oral administration may be provided in solid, semi-solid or liquid dosage forms for oral administration. Oral administration, as used herein, also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast-dissolving tablets, chewable tablets, capsules, pills, bars, lozenges, troches, cachets, pills, medicated chewing gums, bulk powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, wafers, sprays, elixirs, and syrups, and pharmaceutical compositions may contain, in addition to the active ingredient, one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and sources of carbon dioxide.

Suitable binders or granulators include, but are not limited to, starches such as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH)

) The method comprises the steps of carrying out a first treatment on the surface of the Gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as gum arabic, alginic acid, alginates, lichen planus extract, panwar gum, ghatti gum, mucilage of the isabgol shell, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), and the like>

Larch arabinogalactan, tragacanth powder and guar gum; cellulose, such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), and microcrystalline cellulose, for example->

PH-101、/>

PH- 103、/>

PH-105 and->

RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies with the type of formulation and will be readily discernable to one of ordinary skill in the art. In the pharmaceutical compositions provided herein, the binder or filler may be present from about 50% to about 99% by weight.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starches, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can impart certain compressed tablets with properties that allow disintegration in the mouth by chewing. Such compressed tablets may be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernable to one of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar, bentonite, cellulose, such as methylcellulose and carboxymethylcellulose; wood products, natural sponges, cation exchange resins, alginic acid, gums, such as guar gum, and

HV; citrus pulp, crosslinked cellulose, such as crosslinked carboxymethyl cellulose, crosslinked polymers, such as crospovidone; crosslinked starch, calcium carbonate, microcrystalline cellulose, such as sodium starch glycolate, potassium polacrilate; starches, e.g. cornStarch, potato starch, tapioca starch, pregelatinized starch, clay, and algae. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may comprise from about 0.5 to about 15% or from about 1 to about 5% by weight of the disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glyceryl behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil, soybean oil and the like; zinc stearate, ethyl oleate, ethyl laurate, agar, starch; pinus koraiensis and silica gel or silica gel, e.g.

200 and->

The amount of lubricant in the pharmaceutical compositions provided herein varies with the type of formulation and will be readily discernable to one of ordinary skill in the art. The pharmaceutical compositions provided herein may comprise from about 0.1 to about 5 weight percent of the lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide,

And asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified, water-soluble FD&C dye and water insoluble FD suspended on alumina hydrate&C dyes and lakes. Lakes are combinations of dyes that form an insoluble form by adsorbing a water-soluble dye onto a hydrated oxide of a heavy metal. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends which impart a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame . Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite and surfactants, for example polyoxyethylene sorbitan monooleate (+.>

20 Polyoxyethylene sorbitan monooleate 80 (-)>

80 Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, and +.>

Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parahydroxybenzoates, benzoic acid, sodium benzoate, and alcohol. Suitable humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids for use in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. />

It will be appreciated that many carriers and excipients can serve multiple functions, even in the same formulation.

The pharmaceutical compositions provided herein for oral administration may be provided as compressed tablets, abrasive tablets, chewable lozenges, fast-dissolving tablets, composite compressed tablets or enteric coated tablets, sugar coated tablets or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Dragees are compressed tablets coated with sugar, which may help mask unpleasant tastes or odors and protect the tablets from oxidation. The film-coated tablet is a tablet covered with a thin layer of water-soluble material or film. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made through more than one compression cycle, including layered tablets, compressed coated tablets, or dry coated tablets.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administration may be provided in the form of soft or hard capsules, which may be made of gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as Dry Filled Capsules (DFCs), are composed of two parts, one part sliding over the other, thereby completely enclosing the active ingredient. Soft Elastic Capsules (SEC) are a soft spherical shell, such as a gelatin shell, which is plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl p-hydroxybenzoates, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent nos. 4328,245, 4409,239 and 4410,545. The capsules may also be coated as known to those skilled in the art to alter or maintain dissolution of the active ingredient.

Pharmaceutical compositions provided herein for oral administration may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethylene glycol. Elixirs are clear, sugared and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar (e.g., sucrose) and may contain a preservative. For liquid dosage forms, for example, the polyethylene glycol solution may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate metered administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing an active ingredient and a dialkylated mono-or polyalkylene glycol, including 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of polyethylene glycol. These dosage forms may also contain one or more antioxidants such as Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulphite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration may be provided in non-effervescent or effervescent, granular and powder forms to reconstitute liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents may be used in all dosage forms described herein.

Pharmaceutical compositions provided herein for oral administration may be formulated in immediate or modified release dosage forms including delayed release, sustained release, pulsatile release, controlled release, targeted release and programmed release forms.

A process for preparing a compound of formula (I') or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of formula (II'):

with a compound of formula (III):

providing a compound of formula (I') in a solvent and in the presence of a base,

wherein the method comprises the steps of

R ₁ Is H, C ₁ -C ₄ Alkyl, or-C (=O) O- (C) ₁ -C ₄ An alkyl group);

R ₂ is H or C ₁ -C ₄ An alkyl group;

R ₃ is that

-NH ₂ ,-NHC(＝O)Me,/>

Or->

R ₇ Is H or hydroxy;

R ₈ is H or hydroxy;

R ₉ is H or hydroxy; and

R ₁₀ is H or hydroxy.

In certain embodiments, provided herein are methods for preparing a compound of formula (I):

Comprising reacting a compound of formula (II):

with a compound of formula (III):

providing a compound of formula (I) in a solvent and in the presence of a base,

wherein the method comprises the steps of

R ₁ Is H, C ₁ -C ₄ Alkyl, or-C (=o) O- (C) ₁ -C ₄ Alkyl), R ₂ Is H or C ₁ -C ₄ Alkyl group, and

R ₃ is that

-NH ₂ ,-NHC(＝O)Me,/>

In one embodiment, the process is as shown in scheme I below:

scheme I:

in one embodiment, it is assumed that the compound of formula (I') or (I) is not compound 6

In one embodiment, -CH ₂ -R ₃ The group is in the para position to the-NH-group.

In one embodiment, the compound of formula (I) is a compound of formula (I-A):

in one embodiment, CH ₂ -R ₃ The group is in the para position to the-CF 3 group.

In one embodiment, the compound of formula (I) is a compound of formula (I-B).

In one embodiment, the compound of formula (I) is a compound of formula (I-C):

in one embodiment, the compound of formula (I') is a compound of formula (I-D):

in one embodiment, R ₁ Is H. In one embodiment, R ₁ Is C ₁ -C ₄ Alkyl, in one embodiment, R ₁ Is methyl, in one embodiment R ₁ Is tert-butyl, in one embodiment R ₁ is-C (=O) O- (C) ₁ -C ₄ Alkyl), in one embodiment, R ₁ is-C (=O) O- (C) ₁ -C ₄ Alkyl), in one embodiment, R ₁ is-C (=O) OMe, in one embodiment, R ₁ is-C (=o) O-tert-butyl.

In one embodiment, R ₂ Is H, in one embodiment R ₂ Is C ₁ -C ₄ Alkyl, in one embodiment, R ₂ Is methyl.

Exemplary R ₁ 、R ₂ Combinations thereof and corresponding compounds of formula (II) are provided in table 1.

Watch 1 1

In one embodiment, instead of the methyl ester of formula (II ') or (II), the corresponding acid compound (e.g., compound 39) may be used to react with a compound of formula (III) to prepare compound formula (I') or (I) or a pharmaceutically acceptable salt thereof.

Exemplary R ₃ And the corresponding compounds of formula (III) are provided in table 2.

TABLE 2

/>

In one embodiment, provided herein are compounds of formula (I-D):

wherein:

R ₇ is H or hydroxy;

R ₈ is H or hydroxy;

R ₉ is H or hydroxy;

R ₁₀ is H or hydroxy; and

provided that R ₇ 、R ₈ 、R ₉ And R is ₁₀ At least one of which is a hydroxyl group;

or a pharmaceutically acceptable salt thereof.

In one embodiment, R ₇ Is H, in oneIn embodiments, R ₇ Is a hydroxyl group.

In one embodiment, R ₈ Is H, in one embodiment R ₈ Is hydroxy group

In one embodiment, R ₉ Is H, in one embodiment R ₉ Is a hydroxyl group.

In one embodiment, R ₁₀ Is H, in one embodiment R ₁₀ Is hydroxy group

In one embodiment, R ₇ 、R ₈ 、R ₉ And R is ₁₀ At least one of which is hydroxy, in one embodiment R ₇ 、R ₈ 、R ₉ And R is ₁₀ One of which is hydroxy and R ₇ 、R ₈ 、R ₉ And R is ₁₀ The other three of (2) are H.

In certain embodiments, provided herein are methods for preparing a compound of formula (I-a):

wherein the process comprises reacting a compound of formula (II) with a compound of formula 5 to provide a compound of formula (I-a), as shown in scheme II below;

scheme II:

in certain embodiments, provided herein are processes for preparing a compound of formula (I-B) or a pharmaceutically acceptable salt thereof,

wherein the method comprises reacting a compound of formula (II) with a compound of formula 22 to provide a compound of formula (I-B), as shown in scheme III below.

Scheme III:

in certain embodiments, provided herein is a method of preparing a compound of formula (I-C):

wherein the method comprises reacting a compound of formula 4 with a compound of formula (III) to provide a compound of formula (I-C), as shown in scheme IV below: .

Scheme IV:

in some embodiments, provided herein are methods of preparing compound 6 by amidation reaction with a compound of formula 4 and a compound of formula 5 in the presence of a base in a solvent as shown below;

in certain embodiments, provided herein are methods for preparing a compound of formula (I-D), or a pharmaceutically acceptable salt thereof;

Wherein the process comprises reacting a compound of formula (II' -a) with a compound of formula 5 to provide a compound of formula (I-D), as shown in scheme VII below:

scheme VII

In some embodiments, the amidation reaction (e.g., between compound 4 and compound 5, or between a compound of formula (II') or (II) and a compound of formula (III)) may be performed under nitrogen or an inert gas.

In some embodiments, the solvent in the amidation reaction includes, but is not limited to, ether, DMF (N, N-dimethylformamide), N-dimethylacetamide, DMSO (dimethylsulfoxide), N-methylpyrrolidone, toluene, and acetonitrile, or mixtures thereof.

In some embodiments, the solvent in the amidation reaction is ether, DMF, N-dimethylacetamide, N-methylpyrrolidone, or toluene. In some embodiments, the solvent is an ether solvent.

In some embodiments, the ether solvent in the amidation reaction may be THF (tetrahydrofuran), 2-methyltetrahydrofuran, or dioxane. In some embodiments, the ether solvent is THF.

In some embodiments, the amount of solvent in the amidation reaction may be the conventional amount used in amidation reactions in the art, or the amount of solvent is the volume/mass ratio of solvent to compound of formula (1). II') or (II) or formula 4, e.g., (about 5 to about 17) mL:1g, or for example (about 10 to about 15) mL:1g, or (about 15) mL:1g. In some embodiments, the base in the amidation reaction may be an organic base and/or an inorganic base.

In some embodiments, the organic base is, but is not limited to, pyridine, C ₁ -C ₄ Alcohols and/or amines, e.g. -N (R) ₁ )(R ₂ )(R ₃ ) Wherein each R is an alkali metal salt of ₁ 、R ₂ And R is ₃ Independently represents hydrogen or C ₁ -C ₄ An alkyl group.

In some embodiments, C ₁ -C ₄ Alkali metal salts of alcohols are, but not limited to, conventional C's used in amidation reactions in the art ₁ -C ₄ Alkali metal salts of alcohols, such as potassium tert-butoxide and/or sodium tert-butoxide.

In some embodiments, -N (R ₁ )(R ₂ )(R ₃ ) Is Et ₃ N、DIPEA、(i-Pr) ₂ NH and Bu ₃ N, e.g. Et ₃ N or (i-Pr) ₂ NH, usually Et ₃ N。

In some embodiments, the inorganic base is, but is not limited to, an alkali metal carbonate and/or an alkali metal hydroxide.

In some embodiments, the alkali metal carbonate is, for example, K ₂ CO ₃ And/or Cs ₂ CO ₃ 。

In some embodiments, the alkali metal hydroxide is, for example, naOH and/or KOH.

In some embodiments, the amount of base used in the amidation reaction may be conventional amounts used in amidation reactions in the art. In some embodiments, the molar ratio of base to compound of formula (II') or (II) or formula 4 is, for example, (about 1.5 to about 10) 1, for example, (about 1.5 to about 8.0) 1, for example, (about 1.5 to about 6) 1, for example, (about 1.5 to about 5.0) 1

In some embodiments, the base may be added to the reaction mixture in portions during the amidation reaction.

In some embodiments, the molar ratio of the compound of formula (III) or formula 5 to the compound of formula (II') or (II) or formula 4 is, for example, (about 0.8 to about 1.5): 1, for example, (about 0.9 to about 1.3): 1, for example (about 1.2 to about 1.3): 1.

in some embodiments, the reaction temperature of the amidation reaction is in the range of, for example, about-80 ℃ to about 10 ℃, such as about-65 ℃ to about-60 ℃, about-60 ℃ to about-40 ℃, about-30 ℃ to about-20 ℃, about-20 ℃ to about 15 ℃, or about 0 ℃ to about 10 ℃.

In some embodiments, the course of the amidation reaction may be monitored by TLC, HPLC, and other methods known to those skilled in the art. The completion of the reaction can be judged by those skilled in the art based on the scale of the reaction, the conversion of the raw materials, the efficiency of the reaction (i.e., the relation between the yield and the reaction time), the formation of impurities, etc. To obtain the preferred yield and purity. The reaction time is in the range of about 2 hours to about 20 hours, for example about 2 hours to about 12 hours. In some embodiments, the reaction time is from about 2 hours to about 4 hours.

In some embodiments, the post-treatment of the amidation reaction may be a post-treatment commonly used in the art of amidation reactions, and may include washing the reaction solution with water and saturated brine sequentially, removing the solvent, slurrying, adding water, filtering, and drying.

In some embodiments, after the reaction mixture is post-treated with saturated brine, the reaction mixture may be immediately mixed with the amino acid compound before the solvent is removed, and then washed with saturated brine.

In some embodiments, the amino acid compound is cysteine, N-acetyl-L-cysteine, ethylenediamine tetraacetic acid, sodium edetate, and dithiocarbamate, such as cysteine or N-acetyl-L-cysteine, typically N-acetyl-L-cysteine.

In some embodiments, the molar ratio of amino acid compound to compound of formula (II') or (II) or formula 4 is about 0.7 to 1.0:1.

In some embodiments, the method for removing the solvent may be concentrated under reduced pressure.

In some embodiments, the amidation reaction is performed under nitrogen or inert gas, the solvent comprises DMF and/or THF, and the base comprises potassium tert-butoxide, sodium tert-butoxide or Et ₃ The molar ratio of N, base to compound of formula (II ') or (II) or formula 4 is (about 1.5 to 6): 1, the molar ratio of compound of formula (III) or formula 5 to compound of formula (II') or (II) or formula 4 is (about 0.8 to 1.5): 1, and the amidation reaction is carried out at about-60℃to about 10 ℃

In some embodiments, the compound of formula 4 is prepared by deprotecting a compound of formula 3 in a solvent as shown below;

In some embodiments, the deprotection reaction may be performed under a blanket of nitrogen or an inert gas.

In some embodiments, the deprotection reaction may be performed in the presence of an acid. In some embodiments, the acid may be, but is not limited to, hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.

When the deprotection reaction is carried out in the presence of an acid, the solvent may be a conventional solvent used in the deprotection reaction under such conditions, and may be C ₁ -C ₄ Alcohols (e.g. methanol and/or ethanol, typically methanol), chloroalkanes, THF or acetonitrile.

In some embodiments, the deprotection reaction may be performed in the absence of an acid. For example, the deprotection reaction starting material consists of only the solvent and the compound of formula 3.

When the deprotection reaction is carried out in the absence of an acid (for example, the starting material of the deprotection reaction is composed of only a solvent and the compound of formula 3), the solvent may be a solvent commonly used in the present invention. Under these conditions, deprotection reactions occur. Can be but is not limited to acetonitrile, a mixed solvent of acetonitrile and water, or C ₁ -C ₄ A mixed solvent of alcohol and water, wherein C ₁ -C ₄ The mass ratio of alcohol to water is about, for example, 3 to 5:1, C ₁ -C ₄ The alcohol includes, for example, methanol, ethanol, isopropanol, or mixtures thereof, such as methanol and/or ethanol. In some embodiments, the solvent is methanol. In some embodiments, C ₁ -C ₄ The mixed solvent of alcohol and water is, for example, a mixed solvent of methanol and water in a mass ratio of 3:1, and is usually C ₁ -C ₄ A mixed solvent of alcohol and water.

In some embodiments, the mass ratio of solvent to compound of formula 3 in the deprotection reaction is, for example, (about 10 to about 15): 1.

In some embodiments, the reaction temperature of the deprotection reaction is in the range of, for example, about 30 ℃ to about 80 ℃, such as about 60 ℃ to about 80 ℃, about 60 ℃ to about 60 ℃ about 70 ℃, or about 60 ℃ to about 65 ℃.

In some embodiments, the progress of the deprotection reaction may be monitored by TLC, HPLC, and other methods known to those skilled in the art. The completion of the reaction can be judged by those skilled in the art based on the scale of the reaction, the conversion of the raw materials, the efficiency of the reaction (i.e., the relationship between the yield and the reaction time), the formation of impurities, etc., to obtain preferable yields and purities. The reaction time is, for example, in the range of about 10 hours to about 36 hours, such as about 10 hours to about 18 hours.

In some embodiments, post-treatment of the deprotection reaction may include cooling and filtering.

In some embodiments, the temperature to be reached by cooling may be about 20 ℃ to about 25 ℃.

In some embodiments, the post-treatment may also include immediate dry recrystallization, filtration followed by immediate recrystallization, or direct recrystallization without drying. The recrystallization may be performed by dissolving by heating and precipitating by cooling.

In some embodiments, the solvent used for recrystallization is, but is not limited to, e.g., C ₁ -C ₄ Alcohols, further for example, the solvent includes methanol, ethanol, isopropanol, or mixtures thereof. In some embodiments, the solvent is methanol or ethanol. In some embodiments, the solvent is methanol.

In some embodiments, the mass ratio of solvent used for recrystallization to compound of formula 4 may be (about 5 to about 15): 1, for example (about 5 to about 10): 1.

In some embodiments, in the method of heating to dissolve and cooling to precipitate, the dissolution temperature is, for example, in the range of about 50 ℃ to about 70 ℃, for example, about 60 ℃ to about 70 ℃.

In some embodiments, in the method of heating to dissolve the cooled precipitate, the cooling may be slow cooling, rapid cooling, or gradient cooling. In some embodiments, it may be gradient cooling. The temperature can be reduced by about 5 ℃ to 1.5 hours every 1 hour. Gradient cooling may begin at a temperature of about 40 ℃ to about 50 ℃.

The completion of the reaction can be evaluated by those skilled in the art based on precipitation conditions and the like to obtain a preferred yield and purity. The recrystallization time is, for example, in the range of about 8 hours to about 40 hours, such as about 8 hours to about 10 hours.

In some embodiments, the deprotection reaction may be carried out under nitrogen or under an inert atmosphere, and the deprotection reaction may be composed only of a solvent and a compound of formula 3, wherein the solvent is C ₁ -C ₄ Alcohol and water, the temperature of the deprotection reaction is in the range of about 60 ℃ to about 65 ℃.

In one embodiment, the compound of formula (II) is prepared by a process comprising reacting compound 1:

with a compound of formula (IV):

providing a compound of formula (II) in a solvent and in the presence of a base, a catalyst and a catalyst ligand.

In some embodiments, the compound of formula 3 may be prepared by Sonogashira coupling reactions of the compounds of formula 1 and formula 2 in a solvent and in the presence of a base, a catalyst, and a catalyst ligand, as follows:

in one embodiment, the compound of formula (II') is prepared by a process comprising reacting a compound of formula (V):

wherein X is halogen, with a compound having the formula (VI):

providing a compound of formula (II') in a solvent and in the presence of a base, a catalyst and a catalyst ligand.

In one embodiment, X is iodine. In one embodiment, X is bromine. In one embodiment, X is chloro.

In some embodiments, the Sonogashira reaction (e.g., between compound 1 and compound 2, or between compound 1 and the compound of formula (IV), or between the compound of formula (V) and the compound of formula (VI)) can be performed under nitrogen or under an inert gas blanket.

In some embodiments, the solvent in the Sonogashira reaction may be a conventional solvent used in Sonogashira reactions in the art, such as (1) a solvent comprising N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylformamide, acetonitrile, toluene, dioxane, and THF (tetrahydrofuran), (2) N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide, or acetonitrile; in some embodiments, the solvent in the Sonogashira reaction may be a conventional solvent used in Sonogashira reactions in the art, such as (1) a solvent comprising N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide, acetonitrile, toluene, dioxane, and THF (tetrahydrofuran), (2) N-methylpyrrolidone, DMSO (dimethylsulfone), DMF (N, N-dimethylformamide), N-dimethylacetamide, or acetonitrile; or (3) N-methyl-acetone, DMF (N, N-dimethylformamide), or N, N-dimethyl-ethyl-acetone.

In some embodiments, the volume/mass ratio of solvent to compound of formula (IV) or formula 2 is, for example, (about 5 to about 10) mL:1g, for example, (about 7 to about 10) mL:1g.

In some embodiments, in the Sonogashira reaction, the catalyst may be a conventional catalyst used in Sonogashira reactions in the art, such as a palladium catalyst. The palladium catalyst may comprise PdCl ₂ (PPh ₃ ) ₂ 、Pd(dppf) ₂ Cl ₂ 、Pd(dppf) ₂ Cl ₂ And/or palladium on carbon. In some embodiments, the catalyst is PdCl ₂ (PPh ₃ ) ₂ Or Pd (dppf) ₂ Cl ₂ 。

In some embodiments, the molar ratio of catalyst to compound of formula (IV) or formula 2 is, for example, (about 0.01 to about 0.05): 1, for example, (about 0.01 to about 0.03): 1.

In some embodiments, the catalyst ligands for the Sonogashira reaction include, for example, copper compounds and/or triphenylphosphine, in some examples, the copper compounds may be, for example, cuI, cuBr, cu ₂ O, cuO and/or copper acetate in some embodiments, the catalyst ligand is CuI or CuBr.

In some embodiments, the molar ratio of catalyst ligand to catalyst is, for example, (about 0.8 to about 1.2): 1. In some embodiments, the molar ratio of catalyst ligand to catalyst is 1:1.

In some embodiments, in the Sonogashira reaction, the base can be, for example, an organic base and/or an inorganic base.

In some embodiments, the organic base may be a conventional organic base used in Sonogashira reactions in the art, e.g., it comprises pyridine, C ₁ -C ₄ Alkali metal salts of alcohols and/or-N (R) ₄ )(R ₅ )(R ₆ ) Wherein R is ₄ 、R ₅ And R is ⁶ Each of which independently represents hydrogen or C ₁ - C ₄ An alkyl group.

In some embodiments, C ₁ -C ₄ The alkali metal salt of the alcohol may be, but is not limited to, potassium t-butoxide and/or sodium t-butoxide.

In some embodiments, -N (R ₄ )(R ₅ )(R ₆ ) For example, include Et ₃ N、DIPEA、(i-Pr) ₂ NH and/or Bu ₃ N. In some embodiments, -N (R ₄ )(R ₅ )(R ₆ ) Is Et ₃ N or DIPEA. In some embodiments, -N (R ₄ )(R ₅ )(R ₆ ) Is Et ₃ N。

In some embodiments, the inorganic base may be a conventional inorganic base used in Sonogashira reactions in the art, including, for example, alkali metal carbonates and/or alkali metal hydroxides.

In some embodiments, the alkali metal carbonate is, for example, K ₂ CO ₃ And/or Cs ₂ CO ₃ .

In some embodiments, the molar ratio of base to compound of formula (IV) or formula 2 in the Sonogashira reaction is, for example, (about 1.0 to about 1.5): 1. The ratio is (about 1.2 to about 1.3): 1.

in some embodiments, the molar ratio of the compound of formula 1 to the compound of formula (IV) or formula 2 in the amidation reaction is, for example, (about 0.95 to about 2.0): 1, for example, (about 1.2 to about 1.5): 1. In some embodiments, the molar ratio is (about 1.2 to about 1.3): 1.

In some embodiments, the reaction temperature of the Sonogashira reaction is, for example, from about 40 ℃ to about 80 ℃, such as from about 65 ℃ to about 75 ℃, typically from about 65 ℃ to about 70 ℃.

The course of the Sonogashira reaction can be monitored by TLC, HPLC and other methods known to those skilled in the art. Those skilled in the art can evaluate the completion of the reaction according to the reaction scale, the conversion of raw materials, the reaction efficiency (i.e., the relation between the yield and the reaction time), the formation of impurities, etc., to obtain preferable yields and purities. The reaction time is, for example, in the range of about 2 hours to about 12 hours, such as about 2 hours to about 5 hours. In some embodiments, it is from about 2 hours to about 3 hours.

In some embodiments, the work-up of the Sonogashira reaction can be a conventional work-up used in amidation reactions in the art, including mixing with water and filtration.

In some embodiments, the post-treatment of the Sonogashira reaction may further comprise mixing with an amino acid compound prior to mixing with water.

In some embodiments, amino acid compounds for removing heavy metals include, but are not limited to, for example, cysteine, N-acetyl-L-cysteine, ethylenediamine tetraacetic acid, sodium edetate, and/or dithiocarbamate. In some embodiments, the amino acid compound is cysteine or N-acetyl-L-cysteine. In some embodiments, the amino acid compound is N-acetyl-L-cysteine.

In some embodiments, the molar ratio of amino acid compound to compound of formula (IV) or formula 2 is, for example, (about 0.1 to about 0.5): 1.

In some embodiments, the temperature of mixing with the amino acid compound may be in the range of about 35 ℃ to about 45 ℃.

In some embodiments, the mixing time for mixing with the amino acid compound may be from about 4 hours to about 5 hours.

In some embodiments, the mixing temperature for mixing with water may be in the range of about 20 ℃ to about 25 ℃.

In some embodiments, the filtration process may further comprise washing with water.

In some embodiments, the post-treatment of the Sonogashira reaction may further comprise pulping immediately after filtration.

In some embodiments, the solvent used in pulping may be, but is not limited to, ethyl acetate and n-heptane. The volume ratio of ethyl acetate to n-heptane was about 1:1.

In some embodiments, the volume/mass ratio of solvent to coarse filter cake used in pulping may be (about 5 to about 7) mL:1g.

In some embodiments, the Sonogashira reaction can be performed under the protection of nitrogen or inert gas, wherein the solvent is N-methylpyrrolidone, DMF or acetonitrile, and the catalyst is PdCl ₂ (PPh ₃ ) ₂ Or Pd (dppf) ₂ Cl ₂ The molar ratio of catalyst to compound of formula (IV) or formula 2 is (about 0.01 to about 0.05): 1, the catalyst ligand is CuI or CuBr, the molar ratio of catalyst ligand to catalyst is (about 0.8 to about 0.05) about 1.2) 1, and the base is Et ₃ The molar ratio of N, base to compound of formula (IV) or formula 2 is, for example, (about 1.0 to about 1.5): 1, the molar ratio of compound of formula 1 to formula (IV) or formula 2 is, for example, (about 0.95 to about 1.3): 1, and the temperature of the sonogashira reaction is about 65℃to about 75 ℃.

In some embodiments, the compound of formula 4 may be prepared by deprotection of a compound of formula 3 in a solvent as follows:

the reaction conditions for the deprotection reaction can be referred to above.

the conditions of the Sonogashira reaction can be referred to above.

In some embodiments, the invention also provides a compound of formula 3 or a compound of formula 4,

embodiments of the invention may be combined without departing from the common general knowledge in the art.

The reagents and raw materials used in the invention are all commercial products.

In some embodiments, the present invention provides compounds of formula (I') or (I) or formula 6 prepared by the methods described herein.

Without being limited to a particular theory, the advantageous effects achieved by the methods provided herein include the following:

i. The invention adopts a new design route. According to the structural characteristics of the compound 6, the method selects cheap and easily available reaction raw materials, has the advantages of convenient operation, mild reaction conditions, no need of using harsh reaction equipment such as a sealed tube and the like, only needs to simplify post-treatment recrystallization, prevents repeated column chromatography, and can meet the requirement of industrial production.

The invention has novel design route and shorter reaction route. The target product can be obtained only by three steps of reaction. Compared with the existing route, the method shortens the reaction route, reduces expensive and complex raw materials, has the advantages of high yield, good purity, controllable cost and the like, and can effectively ensure the quality of intermediates and subsequent final products.

Amino acid is added for multiple times in the coupling and amidation reaction process in the early stage of the invention, so that excessive heavy metal is prevented, and the heavy metal contained in the active ingredients is ensured in an environment-friendly and effective way. The medicinal components meet pharmacopoeia standards.

The present invention employs a novel design route to obtain two novel intermediates of the compound of formula 3 and the compound of formula 4.

In some embodiments, compounds listed in Table 3 are provided

TABLE 3 Table 3

/>

/>

Detailed Description

Examples

The following examples further illustrate but do not limit the invention. It should be noted that, those skilled in the art may make various modifications and improvements without departing from the inventive concept of the present invention, and all the modifications and improvements are included in the protection scope of the present invention.

Specific conditions not disclosed in the experimental methods of the following examples may be selected according to conventional methods and conditions, or may be selected according to the product specifications.

Unless otherwise indicated, "room temperature" in the following examples refers to 20 ℃ to 25 ℃. The term "h" as used herein refers to hours.

Example 1

Step 1:

n-methylpyrrolidone (137.6 g) was heated to 30 to 35℃under nitrogen protection to give a compound of formula 1 (14.4 g,1.3 eq), a compound of formula 2 (19.14 g,1 eq), bis (triphenylphosphine) palladium dichloride (0.46 g,0.01 eq) and cuprous iodide (0.113 g,0.01 eq) were added in this order, followed by triethylamine (9.45 g,1.5 eq) under nitrogen protection. The reaction mixture was heated to 65 to 75 ℃ and held at that temperature for 2 hours. The process control of the reaction is carried out by liquid phase detection. When the content of the compound of formula 2 is less than or equal to 0.1%, the reaction is terminated. After the completion of the reaction, the reaction mixture was cooled to 35 to 45℃and N-acetyl-L-cysteine (1 g,0.1 eq) was directly added thereto. The reaction was carried out with stirring for 4 to 5 hours. The obtained product was cooled to room temperature, precipitated with water, centrifuged, and washed with pure water to obtain a crude cake. After the coarse filter cake was dried in vacuo, a mixture of ethyl acetate and n-heptane (wherein the volume ratio of ethyl acetate to n-heptane was 1:1, and the mixed solvent of ethyl acetate and n-heptane was 5 mL) was added to the coarse filter cake per gram of coarse filter cake (per gram of coarse filter cake) and made into a slurry. The resulting slurry was dried in vacuo to give the compound of formula 3 in 85.97% yield and 98.2% purity.

The NMR data of the compound of formula 3 were ¹ HNMR(400MHz,d-DMSO):δppm:8.93(1H,d,J＝2.0Hz)；8.63(1H, d,J＝2.0Hz)；8.49(1H,s)；8.11(1H,d,J＝2.0Hz)；7.92(1H,dd,J1＝1.6Hz；J2＝8.0Hz)；7.52(1H,d,J＝8.0Hz)；3.88(3H,s)；2.59(3H,s)；1.65(9H,s).

Step 2:

Methanol (160 g) and water (50 g) were sequentially added to the compound of formula 3 (20 g,1.0 eq) under nitrogen protection, and the reaction system was stirred under reflux for 18 hours and subjected to process control. The resulting product was cooled to room temperature and filtered to give a filter cake (without drying). Adding methanol with the mass 10 times of that of the filter cake for recrystallization, stirring the obtained mixture at 60-70 ℃ for 8-10 h, then cooling to 40-50 ℃, and carrying out gradient cooling process to slowly generate solid precipitate at the cooling speed of 5 ℃ every 1-1.5 hours. The resulting mixture was filtered, the filter cake was washed with methanol and dried in vacuo to give the compound of formula 4 in 91% yield and 99.7% purity.

The NMR data of the compound of formula 4 were ¹ HNMR(400MHz,d-DMSO):δppm:8.73(1H,d,J＝2.0Hz)；8.52(1H, t,J＝2.0Hz)；8.21(1H,d,J＝2.0Hz)；8.06(1H,s)；7.86(1H,dd,J1＝2.0Hz；J2＝8.0Hz)；7.49(1H,dd,J1＝1.6 Hz；J2＝7.6Hz)；3.86(3H,s)；2.56(3H,s).

Step 3:

THF (448 mL), the compound of formula 4 (29.1 g,1 eq) and the compound of formula 5 (24.6 g,0.9 eq) were added under nitrogen and cooled with stirring to-65℃to-60 ℃. At this temperature, potassium tert-butoxide (19 g. Times.3) was added in portions every 0.5 h. The process control of the reaction is carried out by liquid phase detection. After 2 hours, the reaction temperature was raised to-5 to 0 ℃. The reaction solution is washed with purified water, stirred for 0.5 to 1 hour, washed with brine and separated to obtain an organic phase. The organic phase was added N-acetyl-L-cysteine (11.41 g,0.7 eq), stirred, neutralized by washing with brine, concentrated under reduced pressure. The filter cake obtained was washed with purified water and made into slurry. The obtained product was again washed with pure water and dried in vacuo to give the compound of formula 6 in 88.2% yield and 98.6% purity.

The NMR data of the compound of formula 6 were ¹ H NMR(400MHz,d-DMSO):δppm:10.53(1H,s)；8.75(d,J＝2.0)； 8.53(d,J＝2.4)；8.24(1H,s)；8.23(d,J＝2.4)；8.21(d,J＝1.6)；8.09(dd,J1＝1.6；J2＝8.4)；7.94(dd,J1＝2.0；J2＝8.0)； 7.71(d,J＝8.8)；7.53(d,J＝8.0)；3.56(2H,s)；2.59(3H,s)；2.34-2.35(8H,m),2.16(3H,s).

The carbon spectrum data is that ¹³ C NMR(100MHz,d-DMSO):δppm:20.38,45.65,52.64,54.67,57.41,88.26, 91.86,111.76,113.98,117.19,122.14,123.43,127.35(q),124.30(q),128.10,129.89,130.49,131.15,132.02,132.13,132.93,133.66,138.15,143.65,150.55,164.64.

Example 2

The Sonogashira reaction was carried out with reference to the reaction parameters of the rows of table 4 (other parameters are the same as in the first step of example 1), and the calculated yields according to the compounds of formula 2 are shown in the last column of table 4.

Table 4

/>

Example 3

Amidation reactions were carried out with reference to the reaction parameters of the rows of Table 5 (other parameters are the same as in the third step of example 1), and the yields calculated as molar amounts of the compounds of formula 4 or 5 are shown in the last column of Table 5.

TABLE 5

/>

EXAMPLE 4 preparation of Compound 8

5-bromo-2-fluoro-4-methylpyridine (25.02 g,131.7mmol,1.0 eq), NBS (46.93 g,263.3mmol,2.0 eq), AIBN (4.52 g,26.3mmol,0.2 eq), HOAC (1.61 g) were dissolved in CAN (300 mL) and heated to reflux for 8 hours, the organic phase was concentrated to dryness and purified by column chromatography (n-heptane: EA=50:1) to give an orange oil (30.15 g).

A mixture of the oil product obtained in the previous step (20.53 g,76mmol,1.0 eq), calcium carbonate (40.15 g,400mmol,5.3 eq) in 1, 4-dioxane (200 mL) and water (200 mL) was added and reacted overnight at 100 ℃. The reaction solution was cooled to room temperature and filtered. The filtered product was washed with ethyl acetate, and ethyl acetate (200 mL) and water (200 mL) were added to the filtrate. The liquid was separated and the organic phase was collected. The aqueous phase was extracted with ethyl acetate and the organic phases were combined, concentrated to dryness and column chromatographed (DCM: meoh=150:1-100:1-50:1) to give 3.27g of product.

A mixture of the product obtained in the last step (3.22 g,15.6mmol,1.0 eq), DMP (9.93 g,23.4mmol,1.5 eq) in DCM (100 mL) was heated to 25℃and reacted for 1.5 h under nitrogen. After the completion of the reaction, sodium thiosulfate solution (100 mL) and sodium bicarbonate solution (100 mL) were added. The aqueous phase was extracted with ethyl acetate and the organic phases were combined and concentrated to dryness to give a pale yellow oil (3.11 g).

A mixture of the oil product obtained in the previous step (3.02 g,14.8mmol,1.0 eq) and hydrazine hydrate (80%) (0.92 g,14.7mmol, 1.0 eq) was dissolved in 12mL of absolute ethanol under nitrogen and then slowly dropped in portions. After 3 hours of reaction at 25 ℃, the reaction mixture was filtered and dried to give compound 8 (2.08 g).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.33(s,1H),8.24(s,2H),7.81(d,J＝2.1Hz,1H),7.28(d,J＝ 1.5Hz,1H).LC-MS:219.90,217.90.

EXAMPLE 5 preparation of Compound 10

/>

To a mixture of LDA (15 ml,34.81mmol,1.5 eq) and THF (20 ml) under nitrogen was added a solution of 2-fluoro-5-bromopyridine (4.02 g,23.01mmol,1.0 eq) in tetrahydrofuran at-60℃to-70℃and the mixture was stirred for 15 min at-60℃to-70℃and ethyl formate (2.51 g,34.81mmol,1.5 eq) was added and stirred for 20 min at-60℃to-70 ℃. 40mL of a 10% tetrahydrofuran solution was added at-60℃and 30mL of water was added. After the reaction, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to dryness to give 2-fluoro-5-bromopyridine-3-carbaldehyde (4.21 g).

To a mixture of LDA (3.8 ml,8.70mmol,1.5 eq) and 5ml THF was added a solution of 2-fluoro-5-bromopyridine (1.02 g,5.80mmol,1.0 eq) under nitrogen at-60℃to-70 ℃. The mixture was stirred at-60℃to-70℃for 15 minutes, the product obtained in the previous step (1.41 g,6.95mmol,1.2 eq) and 15ml THF were slowly added in several portions at-60℃to-70℃and after stirring for 15 minutes the reaction was carried out at-60℃to-70℃the temperature was controlled below-60 ℃. 10mL of a 10% solution of tetrahydrofuran of citric acid was added followed by 10mL of water. The organic phase was washed with water and sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated to dryness to give a brownish red oil, which was purified by thin layer chromatography to give compound 10 as a pale yellow oil (0.12 g).

¹ H NMR(400MHz,DMSO-d ₆ )8.35(d,J＝2.5Hz,2H),8.33–8.24(m,2H),6.76(d,J＝4.5Hz, 1H),6.00(d,J＝4.4Hz,1H).LC-MS:382.90,381.85,380.80,378.90.

EXAMPLE 6 preparation of Compound 12

To a mixture of LDA (15 ml,34.81mmol,1.5 eq) and THF (20 ml) was added a solution of 2-fluoro-5-bromopyridine (4.02 g,23.01mmol,1.0 eq) in tetrahydrofuran under nitrogen at-60℃to-70 ℃. The mixture was stirred at-60℃to-70℃for 15 minutes, ethyl formate (2.51 g,34.81mmol,1.5 eq) was added and stirred at-60℃to-70℃for 20 minutes. 40ml of a 10% tetrahydrofuran solution was added at-60℃and 30ml of water was added. After the reaction was completed, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to dryness to give 2-fluoro-5-bromopyridine-3-carbaldehyde (4.21 g).

To a mixture of 2-fluoro-5-bromopyridine-3-carbaldehyde (1.57 g,7.34mmol,1.0 eq) and 15ml of anhydrous ethanol, 80% hydrazine hydrate (0.24 g,3.67mmol,0.5 eq) was slowly added dropwise in portions under nitrogen. The reaction was carried out overnight at 25℃and dried by filtration to give compound 12 (0.46 g).

¹ H NMR(400MHz,Chloroform-d)δ8.76(d,J＝1.0Hz,2H),8.70–8.60(m,2H),8.41(dt,J＝ 2.4,1.2Hz,2H).LC-MS:406.90,405.85,404.90,402.90.

EXAMPLE 7 preparation of Compound 19

To a mixture of compound 19-1 (2.0 g) in tetrahydrofuran (19 ml) was slowly added a 1N borane tetrahydrofuran solution (33 ml). The reaction mixture was then heated to reflux, cooled to room temperature and 2N HCl (6 ml) was added. The mixture was refluxed for 1 hour, cooled to room temperature and concentrated to provide a solid. The solid was slurried in a mixed solution of DCM (100 ml) and EtOAc (50 ml) and filtered to provide a solid. The solid was dried under vacuum to afford compound 19-2 (2.14 g).

A mixture of compound 19-2 (0.5 g) and trimethylamine in methylene chloride (20 ml) was cooled to 0℃and a dichloromethane solution of acetyl chloride was added dropwise. After the dropwise addition, the reaction mixture was warmed to room temperature. The organic phase was washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified on a silica gel column to give compound 19.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.13(t,J＝5.2,1H),7.13(d,J＝8.0,1H),6.88(d,J＝2.4,1H), 6.76(dd,J1＝8.4,J2＝2.0,1H,5.48(br,1H),4.22(d,J＝5.2,2H),1.85(s,3H).MS:M+H+＝233.00.

EXAMPLE 8 preparation of Compound 23

A mixture of compound 23-1 (20.11 g,108.04mmol,1.0 eq) and THF (200 ml) was cooled to-20℃to-30℃under nitrogen and DIBAL-H toluene solution (216 ml,1.5mol/l,324.13mmol,3.0 eq) was added slowly in portions. The temperature is kept between-20 ℃ and-30 ℃ for 30 minutes, and then the temperature is increased to 25 ℃ to 30 ℃ for reaction for 4 to 5 hours. Cooled to 0deg.C, isopropyl alcohol (20 ml), saturated potassium sodium tartrate solution (500 ml) and ethyl acetate (500 ml) were added. The aqueous phase was extracted with ethyl acetate (200 ml) and the organic phases were combined and concentrated to dryness to give compound 23-2 (21.7 g).

To a mixture of compound 23-2 (4.0 g,21.16mmol,1.0 eq), ethyl acetate (40 ml) and toluene (4.0 g) was added a 1M HCl solution (20 ml) and stirred for 10 minutes. Sodium hydroxide solution (16 ml 1 m) was added and stirred. The organic phase was washed with sodium chloride solution (50 ml). To the separated organic phase were added p-toluene sulfonic acid (0.44g 2.33mmol,0.11eq), piperazine (1.82 g,21.16mmol,1.0 eq) and ethyl acetate (10 ml). The temperature was cooled to 50deg.C and sodium triacetoxyborohydride (9.64 g,45.49mmol,15 eq.) was added. The reaction time was 1.5 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to the reaction system until no bubbles were released. The solution was separated and the organic phase was concentrated to dryness to afford crude compound 23. The crude product was purified by column chromatography to give compound 23 (0.50 g).

¹ H NMR (400 MHz, chloroform-d) δ7.53 (d, j=8.3 hz, 2H), 6.93 (d, j=2.5 hz, 2H), 6.81 (dd, j=8.3, 2.5Hz,2H),3.76(s,4H),3.55(d,J＝1.7Hz,4H),2.48(s,8H).LC-MS:433.05.

EXAMPLE 9 preparation of Compound 24

Compound 24-1 (15.0 g,80.60mmol,1.0 eq) and THF (150 ml) were mixed. After cooling to-30℃to-40℃DIBAL-H (161.2 ml,1.5m toluene solution, 241.81mmol,3.0 eq) was slowly added in several portions. The temperature is maintained at-30℃to-40℃for 30 minutes, and then at 25℃to 30℃for 3-4 hours. The reaction mixture was cooled to 0 to 10 ℃. The reaction was quenched by the addition of isopropanol (100 ml) and a solution of potassium sodium tartrate was added. The mixture was extracted with ethyl acetate (400 ml), dried and concentrated to give compound 24-2 (15.19 g).

To a mixture of compound 24-1 (15.0 g,80.60mmol,1.0 eq), 1.5g 10% Pd/C and anhydrous methanol (120 ml) was added dropwise a few drops of concentrated hydrochloric acid under nitrogen. The reaction mixture was connected to hydrogen. The reaction was carried out at room temperature for three hours. After filtration, the filtrate was spin dried to provide compound 24-3 (14.9 g).

Under nitrogen, compound 24-2 (15.19 g,80.35mmol,1.0 eq) and compound 24-3 (14.9 g,78.35mol,0.97 eq), sodium triacetoxyborohydride (36.61 g,172.75 mmol), 2 ethyl. Acetate (150 ml) was mixed and heated to 30℃for reaction for 5-6 hours. The reaction solution was quenched with sodium bicarbonate solution to separate the solution and the organic phase was concentrated to dryness. Compound 24 (2.0 g) was obtained by column chromatography.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.15(t,J＝7.9Hz,2H),6.94(dd,J＝8.1,1.2Hz,2H),6.86(dd, J＝7.7,1.2Hz,2H),5.57(s,4H),3.77(s,4H).LC-MS:364.00.

EXAMPLE 10 preparation of Compound 29

To a mixture of sulfuric acid, iodine (0.88 eq) and sodium periodate (0.44 eq) was added p-toluic acid (1.0 eq). The reaction was kept at room temperature for 2-3 hours, then the reaction solution was poured into ice water, stirred, and filtered. Recrystallizing the filter cake with ethanol to obtain a compound 29-1.

Compound 29-1 was dissolved in methanol and sulfuric acid and heated to reflux. The reaction solution was concentrated to dryness and then dissolved in ethyl acetate. The organic phase was washed with sodium bicarbonate solution, partitioned, dried, filtered and concentrated to provide compound 29-2.

Compound 29-2 (1.0 eq) was dissolved in ethyl acetate, and then trimethylsilylene (3.0 eq), bis (triphenylphosphine) palladium dichloride (0.02 eq), cuprous iodide (0.02 eq), and triethylamine (6.0 eq) were added to the reaction solution. The organic phase was washed with water and saturated brine, separated, dried, filtered and concentrated to afford compound 29-3.

Compound 29-3 was dissolved in methanol, cooled, and then potassium carbonate was added. The reaction was completed at room temperature. Cold water was added to the reaction solution, and dichloromethane was extracted. After separation, the organic phase is dried, filtered, concentrated and purified by column chromatography to afford compound 29.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.92(s,2H),4.60(s,2H),3.86(s,3H),2.55(s,3H).MS: M+H ⁺ ＝199.10.

EXAMPLE 11 preparation of Compounds 33 and 34

A mixture of bis (triphenylphosphine) palladium dichloride (0.31 g), cuprous iodide (84 mg) and triethylamine (6.71 g) was added to compound 33-1 (10 g) and acetonitrile (76 g) under nitrogen. The reaction mixture was stirred at 60-70 ℃ for 20 hours, and then directly filtered through silica gel to obtain a dark green liquid. The dark green liquid was concentrated, taken up in n-heptane for 20 hours and filtered to give compound 33.

Compound 33: ¹ H NMR(400MHz,DMSO-d ₆ ):δ7.92(d,J＝9.2,2H),7.86(d,J＝7.6,2H),7.45(m, 2H),6.06(s,1H),5.78(s,1H),3.84(s,J＝6.0,1H),2.42(s,3H).MS:M+H ⁺ ＝349.20.

compound 34 may be isolated from the preparation of compound 33 or from the methods described herein.

Compound 34: ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.77(s,1H),8.09(s,1H),7.88～7.99(m,4H),6.47 (s,1H),6.27(s,1H),5.39(s,1H),3.93～3.98(m,6H),3.84(d,J＝9.2,3H),2.47(s,3H),2.40(s,3H),2.14(s, 3H).

EXAMPLE 12 preparation of Compound 35

Compound 35 can be prepared in a similar manner to the procedure described in international publication No. WO2009/143404 (e.g., pages 107-108) and international publication No. WO2010/124047 (e.g., page 50), the entire contents of which are incorporated herein by reference.

Compound 35 may also be isolated from the methods described herein.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.76(s,1H),8.63(s,1H),8.49(s,1H),8.09(s,1H),7.89(d,J＝8.4, 1H),7.51(d,J＝7.6,1H),3.88(3H,s),2,58(s,3H),1.71(s,9H).

EXAMPLE 13 preparation of Compound 36

Compound 4 (2 g) was mixed with anhydrous tetrahydrofuran (50 mL), cooled to 0 ℃, and sodium hydride (328 mg) was added. The reaction mixture was then stirred at 0℃for 1 hour, followed by addition of methyl chloroformate (777 mg). After the dropping, the temperature was raised to 20℃and stirred for 48 hours. Water (20 mL) was added to stop the reaction. The mixture was stirred and filtered to provide compound 36 as a white solid,

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝2.0,1H),8.64(d,J＝2.0,1H),8.55(s,1H),8.11(s,1H), 7.91(d,J＝7.6,1H),7.53(d,J＝8.0,1H),4.06(3H,s),3.87(3H,s),2,59(s,3H).MS:M+H ⁺ ＝350.1.

EXAMPLE 14 preparation of Compound 37

/>

Sodium hydride (329 mg) was added to a mixture of compound 4 (2 g) and anhydrous tetrahydrofuran (50 mL) at 20 ℃. The reaction mixture was stirred at 25℃for 1 hour. Methyl iodide (1.95 g) was added dropwise thereto, and the reaction mixture was stirred at 20℃for 17 hours, followed by filtration to obtain a crude product. The crude product was slurried in tetrahydrofuran and filtered to provide compound 37.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.79(s,1H),8.52(s,2H),8.07(s,1H),7.88(d,J＝7.6,1H),7.51(d, J＝7.2,1H),4..22(3H,s),3.86(3H,s),2,50(s,3H).MS:M+H ⁺ ＝306.2.

EXAMPLE 15 preparation of Compound 38

Potassium tert-butoxide (2.73 g) was added thereto. The reaction mixture was stirred at-66 ℃ to-70 ℃ for 3 hours. When the temperature was raised to room temperature, 1ml of water was added to stop the reaction. 20ml of 15% brine was added and stirred for 1 hour. After delamination, the organic layer was washed twice with 15% brine. After delamination, a yellow solution was obtained. After adding 20ml of water, the mixture was concentrated to 30ml, and 10ml of ethanol was added thereto. After stirring for 1 hour, the mixture was filtered to give compound 38 as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.9(br,2H),10.55(s,2H),8.74(s,2H),8.54(s,2H),8.21(m, 6H),8.11(d,J＝8.0,2H),7.93(t,J＝8.0,2H),7.83(d,J＝8.4,2H),7.53(d,J＝8.4,2H),3.87(4H,s),2.59(3H, s),2,53(s,3H).MS:M+H ⁺ ＝882.4.

EXAMPLE 16 preparation of Compound 39

Sodium hydroxide (6.4 g) was dissolved in 40ml of water, and compound 3 (5 g) and 40ml of tetrahydrofuran were added. The reaction mixture was stirred at room temperature for 41 hours. After filtration, the filtrate was dried at 40 ℃ to give compound 39 as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.9(br,1H),10.55(s,2H),8.73(s,1H),8.53(s,1H),8.21(s, 1H),8.06(d,J＝1.6,1H),7.85(m,1H),7.47(d,J＝8.0,2H),2.56(3H,s).

EXAMPLE 17 preparation of Compound 40

Compound 40-1 (294 mg) was dissolved in tetrahydrofuran (7 ml), to which compound 4 (250 mg) was added, and the reaction solution was cooled to-77 ℃. 520mg of potassium tert-butoxide are added and the reaction is stirred for 5 hours at-77 ℃. The reaction solution was purified by column chromatography to obtain compound 40 (60 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ13.96(br,1H),10.57(s,1H),8.74(s,1H),8.54(s,1H),8.27(m,3H), 8.11(s,J＝8.0,1H),7.91(t,J＝8.0,1H),7.58(m,2H),7.36(d,J＝8.4,1H),6.79～6.84(m,3H),4.43(s,2H),3.60(s, 2H),2.16～2.67(m,14H).MS:M+H ⁺ ＝706.3.

EXAMPLE 18 preparation of Compound 41

Preparation of Compound 41-1 20.00g of Compound 2, 158mL of NMP, 41.80g of trimethylsilylacetylene, 2.35g of Pd (PPh ₃ ) ₂ Cl ₂ 0.6380g CuI, 13.00g DIPEA. The reaction mixture was heated to 60-70 ℃ under nitrogen and stirred for 5 hours. After the reaction was complete, the reaction mixture was cooled to 5 ℃, etOAc and water were added. The mixture was stirred, separated, extracted, and the organic phases were combined, concentrated and purified by column chromatography to afford 15.40g of compound 41-1 (yield: 72.8%). ¹ H NMR(400MHz, DMSO-d ₆ )δ8.74(d,J＝2.1Hz,1H),8.48(d,J＝2.1Hz,1H),8.43(s,1H),1.63(s,9H),0.27(s,9H).

Preparation of Compound 41 14.86g of Compound 41-1 and 150ml of methanol were added sequentially, cooled to 0-5℃and 9.76g of potassium carbonate were added in portions. Naturally heating to 10-15deg.C after the addition, reacting for 30-45min, slowly adding water to precipitate solid, maintaining for 30-45min, and filtering. The cake was washed with water to pH 7-8 and dried to give 6.50g of compound 41 as a powdery solid (yield: 96.4%).

EXAMPLE 19 preparation of Compound 42

Preparation of Compound 42-2 Compound 42-1 (3.00 g), carbon tetrachloride (50 ml), NBS (2.89 g), AIBN (356 mg) and potassium carbonate (1.65 g) were added in this order, heated to 60-70℃overnight, and stirred for 15-19 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was concentrated to dryness under reduced pressure to give crude compound 42-2 (4.35 g). MS [ M+H ]] ⁺ ＝356.9.

Preparation of Compound 42-3 Compound 42-2 (4.35 g), sodium formate (3.17 g), ethanol (180 ml), and water (48 ml) were added in this order, heated to 80-90℃overnight, and stirred for 15-20 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added, stirred and separated. The organic phase was concentrated to dryness under reduced pressure to give a crude product (3.52 g) of compound 42-3. Purifying the crude product with silica gel column to obtain compound 42-3 (1.20 g), and obtaining 33% MS [ M+H ]] ⁺ ＝293.0.

Preparation of Compound 42-4 Compound 42-3 (1.70 g), compound 41 (833 mg), pd (PPh) ₃ ) ₂ Cl ₂ (327 mg), cuI (89 mg), DIPEA (1.13 g) and NMP (50 ml), heated to 60-65℃and stirred under nitrogen overnight for 10-15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and 2-methyltetrahydrofuran and water were added and stirred. The layers were separated, the organic phase was washed with water, concentrated to dryness under reduced pressure, and purified on a silica gel column to give compound 42-4 (0.96 g) in 54% yield. MS [ M+H ] ] ⁺ ＝308.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.94(s,1H),8.74(q,J＝2.4,1.7Hz,1H),8.54(t,J＝1.7Hz, 1H),8.23(s,1H),8.07(s,1H),8.01(d,J＝8.0Hz,1H),7.74(d,J＝8.1Hz,1H),5.58(t,J＝5.6Hz,1H),4.84 (d,J＝5.4Hz,2H),3.88(s,3H).

Preparation of Compound 42 t-BuOK (1790 mg) is dissolved in THF (14 ml) for later use. Compound 42-4 (700 mg), compound 5 (623 mg) and THF (30 ml) were added, cooled to-60℃under nitrogen, then a solution of t-BuOK in THF was slowly added dropwise, the temperature being controlled at-60 ℃. After the completion of the dropwise addition, the temperature was kept at-60℃and stirred for 1 hour. After the reaction was completed, the temperature was raised to-10 ℃, water and ethyl acetate were added, and the mixture was stirred and layered. The organic phase was concentrated and dried under reduced pressure, and purified on a silica gel column to give 490mg of crude product. The crude product and absolute ethanol were heated to reflux, stirred for 30 minutes, then cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was dried in a vacuum oven at 40 ℃ for 10-13 hours to give compound 42 (270 mg) as a white solid in 20% yield. MS [ M+H ]] ⁺ ＝549.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.95(s,1H),10.58(s,1H),8.74(t,J＝1.6Hz,1H),8.54(t,J＝ 1.6Hz,1H),8.27–8.16(m,3H),8.06(dd,J＝15.4,8.3Hz,2H),7.73(dd,J＝10.9,8.3Hz,2H),5.54(t,J＝ 5.7Hz,1H),4.86(d,J＝5.5Hz,2H),3.57(s,2H),2.37(d,J＝24.3Hz,8H),2.16(s,3H).

EXAMPLE 20 preparation of Compound 43

Preparation of Compound 43-2: under the protection of nitrogen, 30ml of concentrated sulfuric acid is added, the temperature is reduced to 5-10 ℃, 10.00g of 3-iodine-4-methyl benzoate (compound 42-1) is added, stirring is carried out for 20min at 5-10 ℃, and then fuming nitric acid and concentrated sulfuric acid mixed solution (4.57 g of fuming nitric acid is dissolved in 10ml of concentrated sulfuric acid, and the temperature is controlled at 5-10 ℃). After the addition was completed, the reaction mixture was warmed to room temperature, poured into water, DCM was added, the layers were separated, and the organic phase was collected and extracted. The combined organic phases were washed with water, concentrated to dryness, and the crude product was purified by column chromatography to give 2.00g of Compound 43-2 (yield: 17.2%) ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(d,J＝1.8Hz,1H), 8.32(d,J＝1.7Hz,1H),3.90(s,3H),2.56(s,3H).

Preparation of Compound 43-3 1.78g of Compound 43-2, 20ml of ethanol, 1.39g of iron powder, 0.3110g of ammonium chloride and 4.19g of aqueous solution were added in this order under nitrogen protection. The reaction mixture was stirred, heated to 80-90 ℃ and reacted for about 1-1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with DCM, and saturated aqueous sodium bicarbonate solution was added, and the aqueous phase pH was about 8. Stirring the mixture, filtering, separating, and extracting. The combined organic phases were washed with water and concentrated to give 1.60g of compound 43-3 (yield: 99.1%) which was used directly in the next step.

Preparation of Compound 43-4 by adding 15ml of water under nitrogen protection, cooling to-5 ℃ to 5 ℃ and sequentially adding 1.37g of concentrated sulfuric acid, 1.00g of Compound 43-3 and 15ml of ethanol. An aqueous solution of sodium nitrite (0.0618 g of sodium nitrite dissolved in 200ul of water) was slowly added with stirring at 0-5℃and the temperature was maintained. The reaction mixture is heated to 80-90 ℃ and refluxed for 30-45min. After the reaction was complete, the reaction mixture was diluted by adding DCM, layered and extracted. The combined organic phases were washed with alkali, water, concentrated and purified by column chromatography to give solid compound 43-4 (0.77 g).

Preparation of Compound 43-5 under the protection of Nitrogen, compound 43-4 (0.715 g), NMP (20 ml), compound 41 (0.876 g), pd (dppf) Cl were added sequentially ₂ (0.358 g), cuI (93 mg) and DIPEA (3.16 g). The reaction mixture was heated to 90-95℃and reacted for 5-7 hours. After the reaction was completed, the reaction mixture was cooled to 20 ℃, quenched with water, and extracted with 2-methyltetrahydrofuran. The organic phases are combined, concentrated to dryness and purified by column chromatography to obtain crude products. The crude product was washed with ethyl acetate, cooled to room temperature, n-heptane was added dropwise, stirred, filtered and dried to give compound 43-5 (0.62 g), purity 83%, yield 82%.

Preparation of Compound 43-5 (0.60 g), compound 5 (0.53 g) and THF (15 ml) were added sequentially under nitrogen. Cooled to-55℃and 1.0M potassium tert-butoxide in THF (23.4 ml) was slowly added dropwise. After the addition was completed, the reaction was continued for 10 to 15 hours. After the reaction is completed, adding 14% potassium dihydrogen phosphate solution to pH 8-9, extracting with ethyl acetate, washing the organic phase with water, separatingThe layers are washed with an organic phase and purified by column chromatography to obtain a crude product. The crude product was stirred with THF (9 ml), petroleum ether (15 ml) was added dropwise, stirring was continued for 20-30 minutes, filtration and drying were carried out to give compound 43 (0.334 g), purity 99%, yield 32%. ¹ H NMR(400MHz,DMSO-d ₆ ) δ13.94(s,1H),10.50(s,1H),10.08(s,1H),8.72(d,J＝2.0Hz,1H),8.52(d,J＝1.9Hz,1H),8.25–8.18 (m,2H),8.07(dd,J＝8.6,2.1Hz,1H),7.75–7.67(m,2H),7.44(d,J＝1.7Hz,1H),3.58(s,2H),2.42(s,10H),2.22(s,3H).MS:[M+H] ⁺ ＝549.10.

EXAMPLE 21 preparation of Compounds 44 and 45

Methyl 2-hydroxy-4-methylbenzoate (15.25 g) and DCM (100 ml) were added sequentially under nitrogen, cooled to 0-5℃and NIS (19.82 g) was added. After the addition was completed, the reaction mixture was warmed to 20-25℃and stirred for 20-22 hours. After completion of the reaction, water and DCM were added and the layers separated. The organic phase was washed with water, concentrated to dryness and purified by column chromatography to give 15.10g of the product (methyl 2-hydroxy-4-methylbenzoate, compound 44-1 and compound 45-1 as a mixture).

5.10g of a mixture of Compound 45-1, NMP (30 ml), compound 41 (1.0 g), pdCl were added in this order ₂ (PPh ₃ ) ₂ (0.39 g), cuI (0.11 g) and DIPEA (1.36 g). The reaction mixture was heated to 60-66 ℃ under nitrogen protection for 3-5 hours. After completion of the reaction, the reaction mixture was cooled to 20-25 ℃, poured into water, extracted with 2-methyltetrahydrofuran (200 ml) and EtOAc (300 ml), the organic phase was concentrated to dryness and purified by column chromatography to give compound 45-2 (1.26 g) in 59% yield.

Compound 45-2 (0.6 g) was dissolved in THF (8 ml) to prepare a THF solution of compound 45-2 for later use. A mixture of compound 5 (0.56 g) and 1.0M potassium tert-butoxide in THF (23.5 ml) was cooled to-55deg.C and compound 45-2 in THF was added dropwise. After the dripping is finished, the reaction mixture is stirred for 15-20 hours under the heat preservation. The temperature was then raised to-30℃and the reaction mixture was stirred for 4-5 hours. After the reaction was completed, water was added thereto, 1M hydrochloric acid was added dropwise to pH7-8, followed by extraction with ethyl acetate. The organic phases are combined, concentrated to dryness and purified by column chromatography to obtain crude products. The crude product was refluxed with ethanol, cooled to room temperature, filtered and dried to give compound 45 (70 mg), purity 78%, yield 6.5%. MS [ M+H ]] ⁺ ＝549.10

¹ H NMR(400MHz,DMSO-d ₆ )δ13.88(s,1H),11.71(s,1H),8.67(d,J＝2.0Hz,1H),8.43(d,J ＝2.0Hz,1H),8.23–8.15(m,2H),8.13(s,1H),7.93(dd,J＝8.5,2.2Hz,1H),7.71(d,J＝8.5Hz,1H),6.84(s,1H),3.60(s,2H),2.55(s,3H),2.46(s,7H),2.32(s,3H).

2.5g of a mixture of Compound 44-1, NMP (20 ml), compound 41 (1.395 g), pd (dppf) Cl were added in succession ₂ (1.424 g), cuI (0.372 g) and DIPEA (5.53 g). The reaction mixture was heated to 90-95 ℃ under nitrogen protection and reacted for 16-18 hours. After the reaction was completed, the temperature was lowered to 20℃and water was added thereto, followed by extraction with 2-methyltetrahydrofuran. The organic phase was concentrated to dryness and purified by column chromatography to give compound 44-2 (1.44 g) with a purity of 86.8% and a yield of 55%.

Compound 44-2 (0.50 g) was dissolved in THF (8 ml) to prepare a THF solution of compound 44-2 for later use. A mixture of compound 5 (0.467 g) and 1.0M potassium tert-butoxide in THF (19.5 ml) was cooled to-55deg.C and a solution of compound 44-2 in THF was slowly added dropwise. After the dripping is finished, stirring the reaction mixture, continuously preserving the heat for 15-20 hours, and finishing the reactionAfter addition of water, 1M hydrochloric acid was added dropwise to pH 7-8, extraction was performed with ethyl acetate, the organic phases were combined, concentrated to dryness, and purified by column chromatography to give the crude product, which was washed with DCM, filtered and dried to give compound 44 (80 mg) with 99% purity and 9% yield [ M+H ]. MS] ⁺ ＝549.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.91(s,1H),10.62(s,1H),9.20(s,1H),8.74(s,1H),8.41– 8.18(m,2H),8.06(d,J＝8.5Hz,1H),7.89–7.73(m,2H),7.68(dd,J＝7.7,1.4Hz,1H),7.25(d,J＝7.7 Hz,1H),3.60(s,2H),2.62(s,3H),2.39(d,J＝26.4Hz,7H),2.17(d,J＝1.4Hz,3H).

Example 23 antiproliferative Activity of selected Compounds in K562 cells

K562/Ku812/MEG-01 cells were seeded into 96-well plates and treated with various concentrations of selected compounds for 72 hours. Cell viability was determined by CTG assay and IC 50 was calculated using GraphPad Prism 8, data points shown as mean + SEM, and results are listed in the table below.

Na=not provided.

Claims

1. A process for preparing a compound of formula (I') or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of formula (II') with a compound of formula (III) in a solvent and in the presence of a base:

providing a compound of formula (I'):

wherein R is ₁ Is H;

R ₂ is hydrogen or C ₁ -C ₄ An alkyl group;

R ₃ is that

Or->

R ₇ Is H or hydroxy;

R ₈ is H or hydroxy;

R ₉ is H or hydroxy;

R ₁₀ is H or hydroxy;

the solvent is ether, DMF, N-dimethylacetamide or toluene;

the base is C ₁ -C ₄ Alkali metal salts of alcohols and/or N (R) _1’ )(R _2’ )(R _3’ ) Wherein each R is _1’ 、R _2’ And R is _3’ Independently represents hydrogen or C ₁ -C ₄ An alkyl group;

the reaction temperature of the reaction is in the range of-80 ℃ to 10 ℃; and

provided that the compound of formula (I') is not compound 6:

2. the process of claim 1, wherein the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane; and/or, the C ₁ -C ₄ The alkali metal salt of an alcohol is potassium tert-butoxide and/or sodium tert-butoxide;

and/or, the N (R _1’ )(R _2’ )(R _3’ ) Is Et ₃ N、DIPEA、(i-Pr) ₂ NH or Bu ₃ N。

3. The method of claim 2, wherein the ether is tetrahydrofuran;

and/or, the N (R _1’ )(R _2’ )(R _3’ ) Is Et ₃ N or (i-Pr) ₂ NH。

4. A method according to claim 3, wherein the N (R _1’ )(R _2’ )(R _3’ ) Is Et ₃ N。

5. A process for preparing a compound of formula (I):

Comprising reacting a compound of formula (II):

with a compound of formula (III):

providing a compound of formula (I) in a solvent and in the presence of a base,

wherein R is ₁ Is H, R ₂ Is H or C ₁ -C ₄ Alkyl, and R ₃ Is that

Or->

The solvent is ether, DMF, N-dimethylacetamide or toluene;

the base is C ₁ -C ₄ Alcohols and/or N (R) _1’ )(R _2’ )(R _3’ ) Wherein each R is an alkali metal salt of _1’ 、R _2’ And R is _3’ Independently represents hydrogen or C ₁ -C ₄ An alkyl group;

provided that the compound of formula (I) is not compound 6:

6. the process of claim 5, wherein the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane;

and/or, the C ₁ -C ₄ The alkali metal salt of an alcohol is potassium tert-butoxide and/or sodium tert-butoxide;

7. The method of claim 6, wherein the ether is tetrahydrofuran;

and/or, the N (R _1’ )(R _2’ )(R _3’ ) Is Et ₃ N or (i-Pr) ₂ NH。

8. The method of claim 7, wherein the N (R _1’ )(R _2’ )(R _3’ ) Is Et ₃ N。

9. The method of any one of claims 1-8, wherein-CH ₂ -R ₃ The radical is in the para position to the-NH-group.

10. The method of claim 9, wherein the compound of formula (I) is a compound of formula (I-a):

11. the method of any one of claims 1-8, wherein-CH ₂ -R ₃ The radical being in-CF ₃ Para to the group.

12. The method of claim 11, wherein the compound of formula (I) is a compound of formula (I-B)

13. The method of any one of claims 1-8, wherein R ₂ Is H or methyl.

14. The method of any one of claims 5-8, wherein the compound of formula (I) is a compound of formula (I-C)

15. The process according to any one of claims 1 to 4, wherein the compound of formula (I') is a compound of formula (I-D)

16. The process of any one of claims 5-8, wherein the compound of formula (II) is prepared by comprising reacting compound 1 with a compound of formula (IV) in a solvent and in the presence of a base, a catalyst, and a catalyst ligand

17. The process of any one of claims 1-4, wherein the compound of formula (II') is prepared by comprising reacting a compound of formula (V) with a compound of formula (VI) in a solvent and in the presence of a base, a catalyst and a catalyst ligand;

wherein X is a halogen atom and wherein,

18. the process of claim 16 or 17, wherein the reaction between compound 1 and the compound of formula (IV) or the reaction between the compound of formula (V) and the compound of formula (VI) is carried out under nitrogen or under an inert gas atmosphere;

and/or the solvent is selected from the group consisting of N-methylpyrrolidone, DMSO, DMF, N, N-dimethylacetamide, acetonitrile, toluene, dioxane and THF;

And/or the volume/mass ratio of solvent to compound of formula (IV) is (5 to 10) mL 1g;

and/or the catalyst is a palladium catalyst;

and/or the molar ratio of catalyst to compound of formula (IV) is (0.01 to 0.05): 1, a step of;

and/or the catalyst ligand is a copper compound and/or triphenylphosphine;

and/or the molar ratio of catalyst ligand to catalyst is (0.8 to 1.2): 1, a step of;

and/or the base is an organic base and/or an inorganic base;

and/or the molar ratio of base to compound of formula (IV) is (1.0 to 1.5): 1;

and/or the molar ratio of compound 1 to compound of formula (IV) is (0.95 to 2.0): 1;

and/or, the reaction temperature is 40 ℃ to 80 ℃;

and/or, post-treatment of the reaction includes mixing with water and filtering.

19. The process of claim 18, wherein in the reaction of compound 1 with the compound of formula (IV) or the reaction of the compound of formula (V) with the compound of formula (VI), the solvent is N-methylpyrrolidone, DMSO, DMF, N, N-dimethylacetamide or acetonitrile;

and/or the volume/mass ratio of solvent to compound of formula (IV) is (7 to 10) mL 1g;

and/or the palladium catalyst is selected from PdCl ₂ (PPh ₃ ) ₂ 、Pd(dppf) ₂ Cl ₂ 、Pd(OAc) ₂ And palladium on carbon;

and/or the molar ratio of catalyst to compound of formula (IV) is (0.01 to 0.03): 1, a step of;

and/or the copper compound is selected from CuI, cuBr, cu ₂ O, cuO and copper acetate;

and/or the molar ratio of catalyst ligand to catalyst is 1:1;

and/or the organic base is pyridine, C ₁ -C ₄ Alkali metal salts of alcohols or-N (R) ₄ )(R ₅ )(R ₆ ) Wherein R is ₄ 、R ₅ And R is ₆ Each of which independently represents hydrogen or C ₁ -C ₄ An alkyl group;

and/or the inorganic base is an alkali metal carbonate and/or an alkali metal hydroxide;

and/or the molar ratio of base to compound of formula (IV) is (1.2 to 1.3): 1, a step of;

and/or the molar ratio of compound 1 to compound of formula (IV) is (1.2 to 1.5): 1;

and/or the reaction temperature is 60 ℃ to 75 ℃;

and/or, the mixing with the amino acid compound is also included before the mixing with water;

and/or the mixing temperature in the water mixing step is 20 ℃ to 25 ℃;

and/or, the filtering further comprises washing with water;

and/or, post-treatment of the reaction further comprises post-filtration pulping.

20. The process of claim 19, wherein in the reaction of compound 1 with the compound of formula (IV) or the reaction of the compound of formula (V) with the compound of formula (VI), the solvent is N-methylpyrrolidone, DMSO, DMF, or N, N-dimethylacetamide;

and/or the palladium catalyst is PdCl2 (PPh 3) 2 or Pd (dppf) 2Cl2;

and/or the copper compound is CuI or CuBr;

and/or C ₁ -C ₄ The alkali metal salt of alcohol is potassium tert-butoxide and/or sodium tert-butoxide;

and/or-N (R) ₄ )(R ₅ )(R ₆ ) Selected from Et ₃ N、DIPEA、(i-Pr) ₂ NH and Bu ₃ N；

And/or the alkali metal carbonate is K ₂ CO ₃ And/or Cs ₂ CO ₃ ；

And/or the alkali metal hydroxide is NaOH and/or KOH;

and/or the molar ratio of compound 1 to compound of formula (IV) is (1.2 to 1.3): 1;

and/or the reaction temperature is 65 ℃ to 70 ℃;

and/or the amino acid compound is selected from cysteine, N-acetyl-L-cysteine, ethylenediamine tetraacetic acid, sodium edetate and dithiocarbamate;

and/or the molar ratio of amino acid compound to compound of formula (IV) is (0.1 to 0.5): 1;

and/or the mixing temperature at which the amino acid compounds are mixed is from 35 ℃ to 45 ℃;

and/or mixing the amino acid compounds for a mixing time of 4 to 5 hours;

and/or the solvent used for pulping is a mixed solvent of ethyl acetate and n-heptane with the volume ratio of 1:1;

and/or the volume/mass ratio of the solvent used for pulping to the coarse filter cake used for pulping is (5 to 7) ml: 1 gram.